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Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration: A Meta-Analysis
Jonathan B Lin1, Stylianos Serghiou2, Joan W Miller1
1Department of Ophthalmology, Mass Eye and Ear and Harvard Medical School, Boston, MA 02114, USA.
Insights
Systemic complement over-activation is present in early/intermediate age-related macular degeneration (AMD) but not in geographic atrophy (GA). This finding suggests complement inhibition may be a therapeutic strategy for early AMD.
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Complement inhibition is a potential therapeutic strategy for age-related macular degeneration (AMD).
- Current understanding of complement pathway dysregulation in AMD and its relation to disease stage is unclear.
- Previous systematic review identified systemic complement activation profiles in early/intermediate AMD, geographic atrophy (GA), and controls.
Purpose of the Study:
- To meta-analyze existing data to quantify complement dysregulation in AMD.
- To determine if systemic complement activation or inhibition differs between AMD stages and controls.
- To provide mechanistic insights for future AMD clinical trials.
Main Methods:
- Systematic review and meta-analysis of seven studies including 710 participants and 23 effect sizes.
- Restricted maximum likelihood estimation was used to quantify complement dysregulation.
- Comparison of systemic complement activation and inhibition levels between early/intermediate nonexudative AMD, GA, and non-AMD controls.
Main Results:
- Patients with early/intermediate nonexudative AMD showed significantly higher systemic complement activation and lower complement inhibition compared to controls.
- No significant differences in systemic complement activation or inhibition were found in patients with GA compared to controls.
- Evidence supports systemic complement over-activation as a feature of early/intermediate nonexudative AMD, but not GA.
Conclusions:
- Systemic complement over-activation is associated with early/intermediate nonexudative AMD.
- Complement dysregulation patterns differ between early/intermediate AMD and GA.
- Findings support complement inhibition as a potential therapeutic strategy for early AMD.
Abstract:
Although complement inhibition has emerged as a possible therapeutic strategy for age-related macular degeneration (AMD), there is not a clear consensus regarding what aspects of the complement pathway are dysregulated in AMD and when this occurs relative to disease stage. We recently published a systematic review describing systemic complement activation profiles in patients with early/intermediate AMD or geographic atrophy (GA) compared to non-AMD controls. Here, we sought to meta-analyze these results to estimate the magnitude of complement dysregulation in AMD using restricted maximum likelihood estimation. The seven meta-analyzed studies included 710 independent participants with 23 effect sizes. Compared with non-AMD controls, patients with early/intermediate nonexudative AMD (N = 246) had significantly higher systemic complement activation, as quantified by the levels of complement proteins generated by common final pathway activation, and significantly lower systemic complement inhibition. In contrast, there were no statistically significant differences in the systemic levels of complement common final pathway activation products or complement inhibition in patients with GA (N = 178) versus non-AMD controls. We provide evidence that systemic complement over-activation is a feature of early/intermediate nonexudative AMD; no such evidence was identified for patients with GA. These findings provide mechanistic insights and inform future clinical trials.
